Maternal consumption of a high-fat diet has been linked to increased risks of obesity and impaired glucose metabolism in offspring. However, the precise epigenetic mechanisms governing these intergenerational effects, particularly during the early stages of offspring development, remain poorly understood. In this study, female C57BL/6J mice were randomly assigned to either a high-fat diet or normal chow diet throughout gestation and lactation. Methylated DNA immunoprecipitation (MeDIP) coupled with microarray analysis was employed to identify differentially methylated genes in the livers of offspring at weaning age. We found that maternal high-fat diet feeding predisposes offspring to obesity and impaired glucose metabolism as early as the weaning period. DNA methylation profile analysis unveiled a significant enrichment of differentially methylated genes within the natural killer (NK) cell-mediated cytotoxicity pathway. MeDIP-PCR validated reduced methylation levels of specific genes within this pathway, including tumour necrosis factor α (TNF-α), phosphoinositide 3-kinase (PI3K), and SHC adaptor protein 1 (SHC1). Consistently, the expressions of TNF-α, PI3K, and SHC1 were significantly upregulated, accompanied by elevated serum TNF-α and interleukin-6 (IL-6) levels in offspring from dams fed with high-fat diet. Moreover, we assessed the expressions of genes associated with NK cell activities, uncovering a notable rise in hepatic granzyme B levels and a trend towards increased CD107a expression in offspring from dams fed a high-fat diet. In addition, methylation levels of TNF-α, PI3K, and SHC1 promoters were inversely correlated with glucose response during glucose tolerance testing. In conclusion, our findings underscore the critical role of the NK cell-mediated cytotoxicity signaling pathway in mediating DNA methylation patterns, thereby contributing to the programming effects of maternal high-fat diet consumption on offspring glucose metabolism as early as the weaning period.

Exercise training is critical for the early prevention and treatment of obesity and diabetes mellitus. However, the mechanism with gut microbiota and fecal metabolites underlying the effects of voluntary wheel running on high-fat diet induced abnormal glucose metabolism has not been fully elaborated. C57BL/6 male mice were randomly assigned to 4 groups according to diets (fed with normal chow diet or high-fat diet) and running paradigm (housed in static cage or with voluntary running wheel). An integrative 16S rDNA sequencing and metabolites profiling was synchronously performed to characterize the effects of voluntary wheel running on gut microbiota and metabolites. It showed that voluntary wheel running prevented the detrimental effects of high-fat feeding on glucose metabolism. 16S rDNA sequencing showed remarkable changes in Rikenella and Marvinbryantia genera. Metabolic profiling indicated multiple altered metabolites, which were enriched in secondary bile acid biosynthesis signaling. In conclusion, our study indicated that voluntary wheel running significantly improved glucose metabolism and counteracted the deleterious effects of high-fat feeding on body weight and glucose intolerance. We further found that voluntary wheel running could integratively program gut microbiota composition and fecal metabolites changes, and may regulate muricholic acid metabolism and secondary bile acid biosynthesis in high-fat fed mice.